Suture treatment and product



Patented Oct. 28, 1952 UNITED STATES PATENT} OFFICE SUTURE TREATMENT ANDPRODUCT John 0. Bower, Wyncote, Pa.

No Drawing; Application June 9, 1948,

' Serial No. 32,030

11 Claims. 1

This invention has to do with hemoglobincontaining surgical sutures. Itembraces methods by which the hemoglobin content of such sutures may befixed, orrather, converted into a form which is taken up relativelyslowly by the human system, and it also embraces the products resultingfrom the performance of those methods, which are new and valuableinstrumentalities for the surgical profession.

The production of hemoglobin-containing sutures has been disclosed by mein various prior applications for Letters Patent, to which referencewillbe made hereinafter. Such sutures are characterized in that theirpresence in living tissue is not accompanied by manifestations of localirritation, and further, in that the body does not react to isolate anddestroy them, as it attacks conventional sutures, but rather acceptsthem and utilizes them in the formation of new tissue. Under certaincircumstances, however, it is desirable to delay this reparativeprocess, lest the physical strength of the suture be impaired beforehealing of the injury has advanced to such a degree that the new tissuesare able to bear the stresses imposed upon them by the weight andmovement of adjacent flesh.

I have discovered thatit is possible to treat hemoglobin-containingsurgical sutures in such a way as to ensure that the healing andbacteriostatic properties of the hemoglobin will not be entirelydissipated until healing has progressed to such a degree as to removethe necessity for these characteristics. I have further discovered thatthis treatment also tends to slowdown the rate at which the structure of'absorbable sutures is incorporated into new tissue.

Furthermore, sutures which have been subjected to the treatment possessmany desirable and novel characteristics, from the physical, in additionto the physiological, point of view. For instance, sutures of thepresent invention have a very smooth surface, almost as smooth as glass,and this means that they can be implanted very easily, with a minimum offriction attendant upon the passing of the suture through the tissues.Since the pull required to draw them through is slight, there is lessrisk of tearing the flesh. Also, the strands are highly flexible, makingfor ease of handlin and tying; yet, upon being tied, the knots neitherslip or loosen. Still further, these sutures have a marked resistance tocontamination and will maintain sterility under circumstances whichwould render most sutures unsafe.

T j ct o y ent o s to i p t to organic surgical sutures containinghemoglobin the properties set forth above, and such other de sirableproperties as may be incident to the treatment herein after described.

The treatment depends for its effectiveness on the presence ofasubstantial amount of hemoglobin in the suture. I have disclosed,inapplication Ser, No. 502,503, filed September 15, 1943, now Patent No.2,493,943, dated January 10, 1950, the incorporation of hemoglobin in asurgical suture by simply steeping a conventional animal orvegetable-fiber suture in a solution prepared from the red-bloodresidue, which remains after the centrifugal extraction of serum orplasma from whole blood. The same application discloses the spinning ofsurgical sutures from redblood' solutions, as rayon is spun. Thesolution used, Whether for steeping or spinning, comprises red-bloodresidue prepared by using chemical means (salt solutions and ethersolutions) and mechanical means (repeated centrifuging and stirring) tobreak up and dissolve most of the structural matter of the red bloodcorpuscle. A clear solution is obtained by filtration.

Application Ser. No. 519,686, filed January 25, 1944, now Patent'No.2,527,210, dated October 24, 1950, discloses a better methodforobtaining the hemoglobin solution, namely, subjecting a quantity ofred-blood residue to instantaneous freezing at temperatures of theorder-of F., and below, the volumelof residue and shape of the containerbeing so proportioned as to ensure the application of intense coldthroughout the mass in a very few minutes. The rate of heat transfercorresponds to that secured by immersing blood residue in a 30 cc. testtube in a bath of hydrocarbon solvent and Dry Ice at 85 F.

Improvedtechniques forspinning sutures consisting substantially entirelyof red-blood residue are disclosed in applications Ser. No.,547,317,filed January 29, 1944, now Patent No. 2,457,804, dated January 4,1949,and Ser. No. 597,949, filed June 6, ,1945, now PatentNo. 2,484,823,dated October 18, 1949.

Improved therapeutic effects maybeimparted to hemoglobin solutions bydissolving therapeue tic agents such as penicillin in them, as disclosed1n application Ser...No. 569,919, filed December 26, 1944, nowPatentNo.'2,47'7,17,1, dated. July 26, 1949, and these effects 111 inhere insutures prepared from such solutions.

Sutures may be, formed from the peritoneal membrane by soaking Strips ofthat membrane in hemoglobin-stroma solutions and then stretching thestrips while consolidating them into cylindrical form. The hemoglobinsolution is incorporated in such sutures not only in the form of animpregnant, but also as a binder, since it is entrained upon the surfaceof the strips before consolidation as well as absorbed into the cellsthereof. This is disclosed in application Ser. No. 525,458, filed March'7, 1944, now Patent No. 2,487,041, dated November 8, 1949.

In short, surgical sutures containing substantial quantities ofhemoglobin have been heretofore produced by me, and it is to suchsutures that my present invention relates. 1

In its simplest aspect, the process of my invention involves no morethan the treatment of a hemoglobin-containing suture with alcohol for afairly substantial time interval. Although the technique is simple, itseffects are highly significant.

strand from its usual state into a distinctly different state,characterized in that the strand takes on a translucent, glassyappearance. This change may be referred to as a visible change, becauseit is perceptible upon careful gross inspection, that is, with theunaided eye especially if a beam of light is passed through the strand.On microscopic examination, it become evident that the peripheralportion of the strand has largely or entirely crystallized. Onspectroscopic examination of the crystalline material, thecharacteristic hemoglobin lines appear. On application of a selectivestain, such as Ma-llorys (acid fuchsin, aniline blue) stain, thehemoglobin stains a bright red.

But it is by no means certain that the crystals consists entirely ofhemoglobin. In fact, I suspect that they are of a relatively complexcharacter, and that with hemoglobin-impregnated fiber-base sutures, theymay comprehend other components of the impregnating solution.Nevertheless, for lack of a better term, this material will be referredto hereinafter as "crystalline hemoglobin, it being understood that bythat term I mean to define the crystalline product resulting from theapplication of alcohol to materials incorporating the residue of ahemoglobin-containing solution.

I assume that the transformation in state which occurs when ahemoglobin-containing suture is immersed in alcohol involves theconversion of the material near the surface of the strand into a. formwhich is relatively impermeable to alcohol, for the rate at which thistransformation proceeds becomes progressively slower as the change instate progresses radially inward. Eventually this inward development ofcrystallization apparently ceases, leaving a core of substantial size,in which there seems to be no perceptible change. It may be that longerimmersion would produce still further change. But as between a strandremoved from the alcohol after five days (120 hours) and one permittedto remain for several weeks, no significant difierence in inwarddevelopment of the crystalline state was noted.

This is illustrated by thefollowing comparison.

A strand of surgical catgut (not chromicized) was steeped in ahemoglobin-stroma solution a (prepared as described above and inapplication Ser. No. 519,686) for twenty-one days. The strand was thendried in sterile air and cut into shorter lengths. These lengths wereplaced in The result of this treatment is the conversion of hemoglobinnear the surface of the One such length, removed at the end of twohours, showed scarcely any evidence of crystallization, even at thesurface of the strand. In another length, allowed to remain in alcoholfor five days, the hemoglobin had crystallized to a depth approximating6% of the diameter of the strand. Crystallization to approximately thesame extent was evident in another length, which had been allowed toremain in alcohol for twenty-five days.

In preparing transverse sections of the suture for microscopicexamination, the sutures are drawn through molten paraifin until theyhave absorbed a sufliciently heavy coat to protect them, and are nextfirmly embedded in a, block of softened parafiin which is then hardened.The sutures can then be cut and stained more or less efiectively.

The reactions of living tissue to the presence of sutures have beenevaluated by implanting short lengths of the sutures to be tested in theabdominal cavity of laboratory animals, preferably in the sub-mucosallayer of the stomach.

After the sutures have been implanted, the stomach is restored to theperitoneal cavity and the edges of the incision are approximated andsutured in the usual way. When the desired time interval has elapsed,the animals are sacrificed, and specimens of tissue containing thestrands are removed, hardened in formalin, embedded in paraflin,sectioned and stained. The sections are cut as nearly as possible atright angles to the path of the suture, so as to approximate a truecross-section. The staining may be done with hematoxylm-eosin, orpreferably with some double or triple stain having a selective effect onhemoglobin. The Mallory stain mentioned above is particularly efiective.The usual cover glass is then applied, care being taken to mark thespecimen in accordance with the identification afforded by coloredthread attached to each suture before implantation. Specimens so stainedand mounted may be studied at different magnifications, and may readilybe photographed with any desired objective.

Using procedures such as outlined above, I have made many comparisons toascertain the nature of the reactions which follow the implanting ofdifferent sutures in living tissue. In one typical series ofcomparisons, I have employed (a) ordinary catgut sutures; (b)chromicized catgut sutures; (c) catgut sutures impregnated with thehemoglobin-electrolyte-stroma solution disclosed in my application Ser.No. 519,686; and (d) catgut sutures impregnated with the hemoglobinstroma solutions of my application Ser. No. 519,686, but having acrystalline sheath, produced in accordance with the disclosure of thepresent application. The hemoglobin-contain.- ing sutures (c) and (d)were prepared by impregnating ordinary (not chromicized) catgut with thehemoglobin containing solution 23 days. Suture (d) was then dried in airfor 2 hours, and then placed in alcoholic solution for 5 days. Thealcoholic solution used contained U. S. P. ethyl alcohol and 5% U. S. P.isopropyl alcohol. At the end of the 5 day steeping period, the sutureswere removed and sterilized in xylene at C. for 1 hour.

The ordinary catgut sutures, at the end of 5 days, had undergonefragmentation. There was a very pronounced degree of leucocyticinfiltration, indicating the presence of pus in substantial amounts. Inthe 8 day specimen, the degree alcohol, and subsequently removedsequentially, 75 of leucocytic infiltration diminished, and asubstantiahpartorthe strand had been digested and destroyed. Inthe 25day specimen, "the strand had almost'entirely disappeared, leavingbehind a capsular ring'of scar tissue. I

The chromicized catgut suturesalso had assumed a fragmentedappearancein'the 5*dayspecimen. Leucocytic infiltration was much :lessmarked. A wide separation was apparent be.- tween the strand and thesurrounding tissue. This is characteristic of the tissue reaction tochromicized catgut sutures, and'is'attributable, I believe,'to the factthat the chromicizingagent is a very powerful poison. Neither theleucocytes amounts." of hemo lobin. 1; It should; be noted thatthe-amount of hemoglobin takenup by anatu-ralfiber .suturesoaked. inhemoglobin-electrolytestroma solution variesin proportion to the.absorptiveness ;of the strand, as well as the time ofximmersion andstrength of -solution.1 :Somecommercial sutures have been tanned andhardened to such a degree that it requires "3113011?- siderable intervalto secure adequate penetration. Other suture materials arehighlyabsorbent, and will: become thoroughly impregnated in very little time.I

nor the tissues themselves can flourishfiinthe I immediate vicinity ofso powerful an'agent; In I the 8-day section, a fairlylarge'portiomof-the chromicizing agent had apparently been dissolved,and leucocytic infiltration was much more apparent. The strand,howevenwaststill to'a alcohol, were very well received by the tissue inwhich they were embedded. The S-d'ayxperiod showed'some fragmentationofthe strand and practically no polymorphonuclear "infiltration.

The 8-day specimen was marked by the develop mentof a very substantialproliferation of fibroconnective tissue. The strand had been ratherthoroughly broken upyand it seemed that-the fibroblasts were actually"utilizing the structure of the strand in the; formation of new tissue..In the -day specimen, the strand had'been so completely. replaced thatit was necessary-to use a magnificationof 970 diametersuinworder to'findany trace of it. The'entiredefect causedby the passage of the suturehadbeen filledwith 'fibro connective tissue. I

Hemoglobin-containing sutures having a Jc'rystalline surface produced inaccordance witlrlthe disclosure of the present application were equallywell received by the tissues. Polymorphonuclear infiltration was minimalinzthe 5 .day specimen,

and in this instance; the strand was practically intact. In the 8 .dayspecimen the strand had been somewhat more extensively broken ,-up,-:no

' before the suture is'steeped-in alcohol.

evidences of leucocyticinfiltration could be-seen.

and the development of fibroblasts in the periphcry of the defect wasplainly apparent. In the'25 day specimen, fibro-connective: tissue hadfsign'ificantly increased. Nonetheless, the central core of the strandremained practically intact, :and.

.although the sheath of crystalline hemoglobin had diminished inthickness, itrwas plainlyto be-seen surrounding the central Core. I

On thebasis of studies such as these, too numerous to recount in detailin this paper. I have the 1 I Non-irritant and. healing properties :are;im-

parted by the hemoglobin, in proportion to the amount present, eventhough it be very smalL- To attain-iresistanceto premature absorption,how-. ever, it seems to-be important to ensure the-presenceof a fairlysubstantial amount of hemoglobin Sutures spun'from hemoglobinsolutionsofcourse contain hemoglobin; in abundance. On the other hand,- catgutsutures which have been permitted to remain in thehemoglobin-electrolyte-stroma solution for no-more than a briefinterval, say 10 or 15: minutes, apparentlydonot absorb'a sufficientamount'of hemoglobin to produce a signifi+ cant degree ofcrystallizatiomupon subsequent steeping in alcohol, no matter howlongthey are steeped. Vegetable-fiber sutures, such as those oflinenand'cotton, and also suturesof silk,;appear to have sufficient capacityfor absorbing the hemoglobin solution to permit them to .pick'wupanample -quantity in significantly shorter-:interabove, the presenceofhemoglobin ensuresfsubstantial-freedom from tissue'i-rritation.Consequently, the longer the hemoglobin persists, the more certainit-becomes that irritant effectszwill not develop during the healingprocess. Crystallizationreduces the rateat whichhemoglobin is.absorbed,zandtherefore by control of the. de-

gree 'ofcrystallization it becomes possible to en sure a-prolongation ofthe non-irritant effect, to match the healing prognosis.

fIn, the second place, crystallization seems to render the surface ofthe strand relatively. impervious to tissue fluids-enzymes, etc. Theseagencies tend to weaken organic sutures. Since they penetrate the outersurface of a crystallized strand lessreadily, their action on'the"organic core of the strand-is eitherpostponed orretarded. Consequentlythe tensile strength of the suture is not quickly lost,- but diminishesvery gradually. By controlling the degree ofcrystallization, it ispossible to ensure the retention of a high degree d of tensile'strengthin tissue to match the healin prognosis. I

' Finally, it has been my observation that'fibrmblastsand-fibro-connective tissue cells appear"- to derive actualnourishment "from hemoglobin. This is autentative conclusion, based onthe observation that the presence of hemoglobin'in living tissue isfollowed by a. very marked proliferation. of new tissue cells.. Such anunusual proliferation of 'iibrocytes is known under the name ofhyperplasia. I But I believe I- am the first-to have associated it withthe presenceof hemoglobin and-to have discovered thatit may beinduced inany given locale,'-;.by introducing hemoglobin .at that. point. Ofccurseitmay-be that the hemoglobinaserves merelysasa oatalyst 7 orStimulant, rather than as a food. Be thatas it may, a more extensivehyperplasia seems to occur if the hemoglobin is not quickly absorbed,but is made available in smaller amounts over a longer time interval. Bycrystallizing the hemoglobin I can promote this action, whereby maximumof ethyl alcohol (by volume) will prove quite satisfactory, but thesteeping time should be increased. Even at strength, crystallizationwill be effected without excessive timeloss, and without serious loss ofhemoglobin. However, it is to be borne in mind that hemoglobin issoluble in water, and that aqueous solutions containing less than 50% ofalcohol (by volume) will leech out fairly substantial amounts of thehemoglobin and will interfere with proper crystallization. For thisreason, the standard aqueous alcohol solution, containing only 41.5% byweight (or 48.9% by volume) of absolute alcohol, is relativelyunsatisfactory. This tendency of that standard alcohol solution todissolve hemoglobin would seem to indicate that alcohol should not beused for treating hemoglobin-containing sutures. It is surprising tofind that the concentrated (U. S. P.) solution produces results somarkedly different.

Although my preference is for solutions of ethyl alcohol, I have foundthat beneficial results can be secured with other medicinal alcohols,such, for instance, as isopropyl alcohol. This may be veryadvantageously blended with ethyl alcohol so as to produce resultspractically equivalent to those given by the ethyl alcohol solution, ata substantial saving in cost. However, it has seemed to me thatisopropyl alcohol is more likely to leave a slightly irritant residueafter heat sterilization of the crystallized suture. For this reason, Irecommend the use of relatively small proportions of isopropyl alcoholin admixture with ethyl alcohol. Where the ratio of ethyl alcohol toisopropyl alcohol is nine parts or more of ethyl and one part or less ofisopropyl, I have found no significant diiference between the'resultsfollowing use of the mixture and the results which follow use of ethylalcohol alone.

. Although tubing (i. e., packaging) of the suture in' alcohol or in analcoholic aqueous solution might seem to be a logical step, I prefer toavoid this. Even a relatively neutral substance such as xylene, causesmarked irritation on being introduced into living tissue, and for thisreason especially I recommend that the sutures be removed from thefixative solution at the end of the treatment, and be sterilized attemperatures suflicient to volatilize the excess of free alcohol.Thereafter they may be tubed in any appropriate fluid. For this purpose,I prefer to use a neutral oil, such as peanut oil. Where the sutureshave been made by impregnating an organic suture base, such a catgut,with hemoglobin, a very bland solution of a sulfonated salt of a higheralcohol or fatty acid may desirably be used.

Such solution, however, have a tendency to cause swelling when appliedto synthetic sutures produced by extruding a hemoglobin solution andspinning it as rayon is spun.

8 on the other hand, the hemoglobin constituent has a bacteriostaticeffect, and this is sufficiently dependable to permit tubing the suturesin vacuo, or even in sterile air. Although this may result in somereduction of flexibility, sutures'so preserved may easily be slightlysoftened, at the time of use, in water. Once the crystallized hemoglobinsheath has been formed, it is, of course, highly resistant to thedissolving action of water.

The amount of hemoglobin present in (as distinct from on) the suturealso affects the rapidity and the extent of crystallization, and theresistance of the suture to premature absorption when implanted inliving tissue.

Catgut sutures which have been steeped in hemoglobin solution fortwenty-five days and have then been kept in the fixative solution forfive days seem to show maximum resistance to absorption. Sections takenbetween sixty and ninety days after the implanting of such sutures stillshow traces of the original suture structure and of very smallhemoglobin crystals. On the other hand, Where the suture has been leftin hemoglobin solution for only a few'hours, dried, and then immersed inthe fixative solution for five hours, no traces of the suture could befound at the end of sixty days, although some evidence of it wasdiscernible in a forty-five day section.

I therefore conclude that it is possible to control the rate ofabsorption of a surgical suture in living tissue by incorporatinghemoglobin in its structure, and subjecting the hemoglobin containingsuture to th action of a fixative solution for intervals of time varyingfrom one hour up to about five days or more. Where the amount ofhemoglobin incorporated in the suture is reduced, the time of exposureto the fixative solution should be increased. The extent ofcrystallization varies in proportion to the amount of hemoglobin presentand the time of exposure to the fixative solution, and the extent ofcrystallization bears a direct relation to the resistance of the strandto absorption in living tissue. This is believed to be a'discovery'ofimportance to' the surgical profession. Heretofore delay in absorptionof surgical sutures has been secured by subjecting them to tannintreatment of various sorts. Most common of these has beenchromatization. But tanning agents, as is very well understood in thisprofession, are cell poibeen destroyed by leucocyticaction are in the.

form of islands, isolated by a substantial space or "halo from thecircumference of the defect produced by passage of the suture. The toxiceffect of the chromicizing agent persists so long as any part of thesuture structure remains, and new cells will not fill in the defectuntil the chromicizing agent has been completely e1iminated. Incontrast, new cells very shortly invade the channel of ahemoglobin-containing suture, and fill in the defect, with little or noevidence of leucocytic infiltration.

I claim:

1.. The method of imparting to an absorbable surgical suture acontrolled resistance to absorption when in living tissue, which methodcomprises the steps of immersin a surgical suture containing asubstantial amount of hemoglobin in an aqueous solution comprising atleast 50% ethyl alcohol, and maintaining it therein at least untilvisible modification of the lightrefractive characteristics of thesurface has occurred, and removing the suture from its alcoholicenvironment when the desired degree of resistance to absorption has beenproduced.

2. The method of claim 1, in which the hemoglobin-containing surgicalsuture is one which has been extrusion spun from a spinning solutioncontaining hemoglobin.

3. The method of claim in which the hemoglobin-containing surgicalsuture is one which has been formed by steeping an organic-fiber suturebase in a hemoglobin-containing solution for from thirty minutes tothirty days until said solution has thoroughly impregnated at least theperipheral portion of the suture base.

4. The method of claim 1, in which the suture is maintained in thealcohol for at least one hour. 5. A method according to claim 1, inwhich A the suture after removal from the alcohol is heated to drive offthe alcohol and is then stored in a suture storing medium free ofalcoholic constituents.

6. A surgical suture having substantial quantities of a materialconsisting essentially of the reaction product of hemoglobin and ethylalcohol incorporated in its surface.

7. A hemoglobin-containing surgical suture characterized by the presenceof hemoglobin in a central core and in a peripheral sheath therefor, thehemoglobin in the core portion being in a more readily soluble statethan that in the sheath, the hemoglobin in the sheath being in a stateconsequent upon treatment with a liquid consisting assentially of ethylalcohol.

8. A surgical suture having an organic fiber basis and having a dense,glossy, water-resistant peripheral portion throughout which hemoglobincrystals are present, said suture being characterized by a relativelyhigher resistance to absorption by body tissues than a surgical sutureof the same composition in which the hemoglobin in the peripheralportion is not in a glossy, Waterresistant state.

9. A non-irritant absorbable surgical suture having an organic fiberbasis and incorporating in its structure an irritation-preventingcompound, said compound being the product resulting from subjecting toreaction with a liquid consisting essentially of ethyl alcohol a suturewhich incorporates the residue of a hemoglobin-containing solution.

10. A surgical suture having an absorbable central core and an adherentperipheral sheath, in which the sheath comprises the reaction product ofhemoglobin and alcohol.

11. The absorbable surgical suture of claim 10, in which the thicknessof the sheath is equal The following references are of record in thefile of this patent:

UNITED STATES PATENTS Number Name Date 794,623 Herbabny July 11, 19052,127,903 Bowen Aug. 23, 1938 2,128,701 Gelinsky Aug. 30, 1938 2,457,804Bower Jan. 4, 1949 2,487,041 Bower Nov. 8, 1949 2,493,943 Bower Jan. 10,1950 OTHER REFERENCES Fieser and Fieser: Organic Chemistry, 1944, D. 0.Heath & 00., pp. 432-436. Copy in Div. 55.

6. A SURGICAL SUTURE HAVING SUBSTANTIAL QUANTITIES OF A MATERIALCONSISTING ESSENTIALLY OF THE REACTION PRODUCT OF HEMOGLOBIN AND ETHYLALCOHOL INCORPORATED IN ITS SURFACE.